Ceritinib is a kinase inhibitor indicated for the treatment of patients with anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer (NSCLC).
Ceritinib is chemically known as 5-Chloro-N4-[2-[(1-methylethyl) sulfonyl]phenyl]-N2-[5-methyl-2-(1-methylethoxy)-4-(4-piperidinyl)phenyl]-2,4-pyrimidinediamine and structurally represented as below.

Ceritinib was disclosed in U.S. Pat. No. 8,039,479 and marketed as ZYKADIA®. US'479 patent disclosed preparation of ceritinib, wherein 2,4,5-trichloro-pyrimidine (XII) is reacted with 2-(isopropylsulfonyl) aniline (XI) to get 2,5-dichloro-N-(2-(isopropyl sulfonyl)phenyl)pyrimidin-4-amine (XIII) and 4-pyridine boronic acid is reacted with 2-chloro-4-isopropoxy-5-nitro-toulene to get 4-(5-isopropoxy-2-methyl-4-nitro-phenyl)-pyridine (XVI), then it is treated with TFA and PtO2 the reaction mixture was stirred and concentrated after workup to get residue. After concentration the crude was dissolved in dichloromethane and TEA and Boc2O was added to get 4-(4-amino-5-isopropoxy-2-methyl-phenyl)-piperidine-1-carboxylic acid tert-butyl ester (XVII).
2,5-dichloro-N-(2-(isopropyl sulfonyl)phenyl)pyrimidin-4-amine (XIII) and 4-(4-amino-5-isopropoxy-2-methyl-phenyl)-piperidine-1-carboxylic acid tert-butyl ester (XVII) were reacted in presence of palladium acetate and Cs2CO3 in THF solvent in a sealed reaction vessel heated with microwave irradiation. After concentration the crude product was purified by silica gel chromatography to give boc protected Ceritinib and this product was dissolved in dichloromethane and TFA and HCl is added causing the product HCl salt to precipitate. The schematic representation is as shown in below scheme-1.

U.S. Pat. No. 9,309,229 discloses the crystalline form A and B of ceritinib. Wherein form A was prepared by reacting 2-isopropoxy-5-methyl-4-(piperdin-4-yl) aniline dihydrochloride and 2,5-dichloro-N-(2-(isopropyl sulfonyl)phenyl)pyrimidin-4-amine in presence of 2-propanol and the mixture was heated to get 5-chloro-N-(2-isopropoxy-5-methyl-4-(piperidin-4-ylphenyl)-N-2-(isopropylsulfonyl)phenyl)-2,4-diamine di-hydrochloride and this dihydrochloride salt was recrystallized using acetone:water.
Further to 5-chloro-N-(2-isopropoxy-5-methyl-4-(piperidin-4-yl)phenyl)-N-(2-(isopropyl sulfonyl)phenyl)-2,4-diamine di-hydrochloride, acetone:water (3:1, v/v) was added at ambient temperature. The mixture was heated to 55±3° C. in about 20 minutes to obtain a clear solution. The hot solution was filtered and acetone and water was added to the mixture. While heating was maintained, aqueous NaOH solution was added over a period and the reaction mixture was maintained at 55±3° C. for an additional 2 hours to yield an off-white slurry. The slurry was cooled to 20±3° C. over a period of about 45 minutes and deionized (DI) water was added over about 30 minutes and the off-white slurry was stirred at 20±3° C. for 1 hour. The slurry was filtered and rinsed with DI water. The wet cake was dried about 17 hours in a vacuum oven at 50±3° C. and 10 mbar under a N2 purge to yield form A of Ceritinib.
Wherein form B was prepared as Ceritinib was dissolved in HCl at 30-40° C. to afford a clear solution. NaOH was added to this clear solution dropwise over 20 minutes at 20-23° C. A cloudy mixture was obtained, which was heated with stirring at 40-42° C. for 2 hours and subsequently heated to 50-55° C. for 2 hours. The resulting slurry was cooled to room temperature and the slurry was filtered. The wet cake was washed with water and dried under vacuum to obtain form B of ceritinib.
The present inventors of the present invention has developed an improved process for the preparation of ceritinib with high yield and high purity. The present process is cost effective and feasible in large scale production also. The present invention also related to a stable amorphous form of Ceritinib and its preparation. The amorphous form of Ceritinib of the present invention is stable up to 180 days. The present invention also relates to a process for the preparation of Crystalline form A of Ceritinib.